Mucopolysaccharidosis-Plus Syndrome

A number sign (#) is used with this entry because of evidence that mucopolysaccharidosis-plus syndrome (MPSPS) is caused by homozygous mutation in the VPS33A gene (610034) on chromosome 12q24.

Description

MPSPS is an autosomal recessive inborn error of metabolism resulting in a multisystem disorder with features of the mucopolysaccharidosis lysosomal storage diseases (see, e.g., 607016). Patients present in infancy or early childhood with respiratory difficulties, cardiac problems, anemia, dysostosis multiplex, renal involvement, coarse facies, and delayed psychomotor development. Most patients die of cardiorespiratory failure in the first years of life (summary by Kondo et al., 2017).

Clinical Features

Dursun et al. (2017) reported 2 sisters, born of consanguineous Turkish parents, with a multisystem disorder resulting in death at ages 6 years and 10 months. Both patients showed early-onset respiratory difficulties with imaging and histopathologic evidence of acute respiratory distress syndrome (ARDS). The older patient presented at age 3.8 years with recurrent respiratory infections and breathing difficulties, whereas the younger sib presented at age 5 months. Both patients had delayed psychomotor development and variable skeletal anomalies consistent with dysostosis multiplex, including beaking of vertebral bodies, J-shaped sella turcica, oar- or paddle-shaped ribs, hip dislocation, hypoplastic acetabulae, flexion contractures of the hands, foot deformities, and pectus abnormalities. The older sib had dysmorphic facial features, including coarse face, low hairline, short neck, large forehead, broad nasal bridge, long eyelashes, synophrys, hirsutism, and macroglossia. She developed pyramidal signs with spasticity and hyperreflexia around age 5 years. Laboratory studies showed dark blue granules in lymphocytes in both patients, but no storage cells in the bone marrow aspirate of the older sib. Urinary analysis did not show mucopolysaccharidosis on the first examination, but showed only small amounts of dermatan sulfate and heparan sulfate on repeat examination. Other features included anemia, hepatosplenomegaly with macrovesicular steatosis, and renal dysfunction with proteinuria. Renal biopsy in both patients showed focal glomerulosclerosis and enlarged glomerular visceral epithelial cells with foamy and granular cytoplasm. Laboratory studies in the older sib showed dark blue granules in lymphocytes, but no storage cells in the bone marrow aspirate, and urinary analysis did not show mucopolysaccharides. Electron microscopy of conjunctiva from the older sib showed abnormal endoplasmic reticulum, large and/or degenerated mitochondria, several glycogen granules, early and late endosomes, multivesicular bodies, and large vacuoles, suggesting dysfunction of the vesicular transport system similar to a lysosomal storage disease.

Kondo et al. (2017) reported 13 children from Yakutia in the Russian Federation with characteristic clinical features of an MPS with significantly increased urinary excretion of glycosaminoglycan (GAG) and increased plasma heparan sulfate, but no lysosomal enzyme deficiencies. The patients presented in infancy with obstructive lung disease accompanied by frequent respiratory infection and congenital heart defects, including patent ductus arteriosus, atrial septal defect, and hypertrophic cardiomyopathy. Eleven patients died of cardiorespiratory failure between 1 and 2 years of age. The patients had coarse facial features, macroglossia, thick skin, barrel-shaped chest, psychomotor retardation, joint contraction, and progressive skeletal dysplasia. Additional features included optic atrophy, hepatosplenomegaly, renal dysfunction with proteinuria, anemia, thrombocytopenia, and leukocytopenia. Three patients had abnormal brain imaging, including delayed myelination, brain atrophy, and cerebral calcification.

Inheritance

The transmission pattern of MPSPS in the families reported by Dursun et al. (2017) and Kondo et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sisters, born of consanguineous Turkish parents, with MPSPS, Dursun et al. (2017) identified a homozygous missense mutation in the VPS33A gene (R498W; 610034.0001). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. Functional studies of the variant were not performed.

In 13 patients from Yakutia in the Russian Federation with MPSPS and significantly increased urinary excretion of glycosaminoglycan, Kondo et al. (2017) identified homozygosity for the R498W mutation in the VPS33A gene. The mutation in the first family was found by whole-exome sequencing, whereas the mutations in the other families were found by direct Sanger sequencing of this mutation. Patient fibroblasts and VPS33A-knockdown HeLa cells showed accumulation of heparan sulfate and over-acidification of lysosomes. However, patient cells showed normal intracellular trafficking with normal endocytic and autophagic function. The findings suggested that VPS33A plays a role in lysosomal functions involved in GAG metabolism.